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Tiffany M. Schmidt, Catherine J. Sheely, Samer Hattar; The Transcription Factor Math5 is Involved in the Development of Only a Subset of iprgcs. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4340.
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© ARVO (1962-2015); The Authors (2016-present)
During eye development, a series of organized processes occur during which all retinal cell types arise from progenitor cells. Expression of various transcription factors at discrete timepoints in development leads to the differentiation of each retinal cell type. Math5 (Atoh7) is a basic helix-loop-helix proneural transcription factor that is necessary for mammalian RGC determination. However, recent results indicate that intrinsically photosensitive (ip) RGCs, which express the photopigment melanopsin and subserve predominantly non-image-forming functions, continue to be generated in the developing retina after Math5 is downregulated. This suggests that some ipRGCs might arise independently of Math5, and led us to examine the role of Math5 in the development of ipRGCs.
We utilized a mouse line in which Cre-recombinase replaced the Math5 gene (Math5Cre) in conjunction with several Cre-dependent reporter lines to examine the proportion and projection patterns of ipRGCs that arise from the Math5 lineage.
Surprisingly, lineage tracing revealed that just 50% of melanopsin-immunopositive cells arise from the Math5 lineage. Despite this partial colabeling between Math5 lineage and ipRGCs, Math5 mutants, lacked 90-95% of both conventional RGCs as well as ipRGCs. To resolve this discrepancy, we investigated whether ipRGCs die secondarily in the absence of Math5 lineage RGCs. We crossed Math5 mutants with animals that lack cell death in neurons via elimination of the proapoptotic factor Bax (Bax-/-). In double knockout animals (Math5-/-; Bax-/-), we observe the expected doubling of surviving RGCs (10%) but observe a 6-fold greater proportion of ipRGCs (~60%) that remain in the Math5-/-; Bax-/- animals. This is in agreement with our lineage tracing data showing a larger proportion of ipRGCs than conventional RGCs are Math5-independent. Finally, we examined the projections of Math5 RGCs to various image-forming and non-image forming targets. We found that Math5 RGCs heavily innervate the suprachiasmatic nucleus (SCN), the structure responsible for driving mammalian circadian rhythms.
Our lineage tracing suggests that approximately half of ipRGCs arise independently of Math5, and indicate that the near complete loss of ipRGCs in Math5 mutant animals is due to secondary cell death. Furthermore, the substantial innervation of the SCN suggests that Math5 lineage ipRGCs likely mediate circadian photoentrainment.
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